Correlation of Functional and Structural Units in Cerebral Cortex This proposal is an expansion of our earlier NIH R21 project that explored the spatial relationship between functional magnetic resonance imaging (fMRI) signals and the underlying neuronal architecture. In a combined high- resolution fMRI and histological study, conducted in the same animal and cortical region, we demonstrated for the first time that tissue fMRI signals peak at cortical layer IV. The spatial specificity of any hemodynamic-based mapping technique is bound by the underlying vascular network;therefore, the spatial relationship between the two is crucial for understanding the mechanisms governing and limiting these mapping techniques. The current understanding of the fMRI contrast mechanism, regarding its vascular origins, is based on numerous assumptions and theoretical modeling, but little experimental validation exists to support or challenge these models. Due to mainly technical limitations, the current knowledge of cerebral vasculature is limited to the large pial surface and capillary level vessels. However, little is known regarding the cluster of intermediate-sized, mainly the intracortical vessels, connecting these two groups and where, arguably, key blood flow regulation takes place. Building on our pervious findings, we will explore the spatial correspondence of fMRI signals with the underlying vascular organization. To accomplish the proposed goal several multimodal developments will be embarked on. A new method for in- vivo visualization and classification (veins and arteries) of cortical vessels will be developed. Utilizing a new and unique ultra high-field (16.4 T / 26 cm) magnet, a high-resolution MRI acquisition schemes combined with ex-vivo micro-CT imaging will enable detailed and accurate 3D modeling of cortical vasculature at resolution approaching the microscopic scale. In addition, analytical tools will be developed to provide morphological description and quantification of the vascular model. Capitalizing on this unique approach, the spatial distribution of stimulus-induced fMRI signal changes will be correlated with the underlying vascular model within the same animal and cortical region. Several hypotheses will be explored with respect to fMRI signals and the cortical vessel morphology such as vessels size and the spatial distributions throughout the tissue. Furthermore, by stimulating only subsets of the neuronal ensemble in primary visual cortex, 3D functional maps of ocular dominance and orientation columns will be generated and correlated with the vascular model. We will investigate whether these functional cortical assemblies are coupled to specific vascular units. The outcome of these studies will be twofold: initially, development of new and unique methodological tools that will provide ways for exploring vascular models. These techniques will be applied to a broad variety of applications that utilize knowledge of the vascular architecture;such application include, but not limited to, fMRI, cerebrovascular diseases, cancer angiogenesis research and models of cerebral thermal regulation all of which will greatly benefit from an accurate vascular model. In the second outcome, neurophysiology research and clinical applications will benefit;with better understanding of the vascular morphology and fMRI mechanism, one can expect the increase in spatial localization and spatial specificity of the fMRI signals to the site of neuronal activity. Clinical applications such as neurosurgery planning, epilepsy and brain tumor resections will all benefit from increased accuracy. Furthermore, if indeed a correlation between functional (neuronal) and structural (vascular) units exist, in the future, it may be used as a diagnostic tool for brain disorders prior to the appearance of any clinical behavioral symptoms. PUBLIC HEALTH RELEVANCE: Functional Magnetic Resonance Imaging (fMRI) is a technique that allows, noninvasively, the localization of active brain regions. Increased neuronal activity in the brain is followed by a small and localized increase in blood flow which can be measured using fMRI. While fMRI has revolutionized the field of human brain research, little is known about the underlying vascular origin of these hemodynamic-based signals. Using a powerful magnet, this study is aims to obtain extremely high-resolution images of cortical vessels, generate a 3-D model of the vascular tree and correlate it with the fMRI signals. The outcome of these studies will greatly enhance our understanding of the vascular network and benefit a variety of research applications including fMRI, cerebrovascular disease, and cancer angiogenesis.